ABSTRACT Acute respiratory distress syndrome (ARDS) is a common, devastating clinical syndrome caused by several direct and indirect insults to the lung, with pneumonia and sepsis being the most common. It is critical that the underlying processes leading to ARDS be identified as early as possible to direct effective targeted therapy. Emerging evidence links the pathogenesis of multiple diseases to gene regulation by microRNAs (miRNAs), the small non-coding RNAs that bind to specific target sites on messenger RNA and either repress or degrade the targets. Although miRNAs play important roles in inflammation and infection, which are common manifestations in ARDS, no study has investigated blood miRNA expression as a biomarker(s) for ARDS risk and/or ARDS-related outcomes. This proposal comprises a case-control study and survival analysis as part of a molecular epidemiology study of ARDS (MEARDS) that enrolled both ARDS patients and at-risk controls from the Intensive Care Units at Massachusetts General Hospital and Beth Israel Deaconess Medical Center in Boston. Our objective is to develop and validate miRNA biomarkers in whole blood of potential utility in early diagnosis, prognosis and treatment of ARDS. In Aims 1 & 2, the participant's blood is drawn within 24 hours of ICU admission. Whole blood miRNA expression will be profiled by Taqman OpenArray human microRNA panel. Strict miRNA quality control procedures and robust statistical analysis will be conducted to identify candidates that are potentially associated with ARDS case-control status and survival. Based on the results, we will construct miRNA panels (miRNA index scores) to strengthen prediction power. Furthermore, using existing genome-wide association study (GWAS) data, in Aim 3, we will explore the impacts of functional single nucleotide polymorphisms (SNPs) on miRNA expression; and, in Aim 4, we will investigate the effects of ARDS-related GWAS loci that are mediated through miRNA expression. The proposed study is innovative as it is the first large-scale study of miRNA biomarkers for ARDSsusceptibility and outcomes. A combination of several markers, miRNA and SNP, will likely improve the diagnostic and prognostic accuracy of individual markers, facilitating the early identification of high-risk patients and ensuring rapid and more effective interventions. In addition, this will be the first large-scale population-based genotype-phenotype study that will generate valuable genetic as well as epigenetic information related to the ARDS biomarker panel.